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Abstract:

The present invention is directed to a pulsatile ophthalmic peri-corneal
drug delivery device. The device includes an annular body and a mechanism
for releasing multiple separate and distinct doses of a therapeutic
composition over an extended period of time.

Claims:

1. An ophthalmic peri-corneal drug delivery device, comprising; an
annular body sized and shaped to reside upon a conjunctiva of a human eye
and extend substantially entirely about a cornea of the human eye when
the annular body is disposed upon the human eye; a therapeutic
composition associated with the annular body; and at least one opening
for releasing the therapeutic composition wherein the therapeutic
composition is released through the at least one opening topically to the
eye as multiple separate doses through repeated release of one or more of
a plurality of separate and distinct units.

2. A device as in claim 1 wherein the therapeutic composition is divided
into the plurality of separate and distinct units within the annular
body.

3. A device as in claim 1 wherein the device, the annular body or both
include a contact surface that is shaped and sized to correspond to and
contact the conjunctiva of the human eye upon application of the device
to the eye.

4. A device as in claim 3 wherein the contact surface of the device
including all portions that contact the conjunctiva has a surface area
that is at least 77 mm2 and is typically no greater than 220
mm.sup.2.

5. A device as in claim 1 wherein the device has a volume that is at
least at least 14 mm3 and is no greater than 100 mm.sup.3.

6. An ophthalmic pericorneal drug delivery device, comprising; an annular
body sized and shaped to reside upon a conjunctiva of a human eye and
extend substantially entirely about a cornea of the human eye when the
annular body is disposed upon the human eye; a therapeutic composition
associated with the annular body wherein the therapeutic composition is
divided into a plurality of separate and distinct units; a plurality of
separate reservoirs, each of the plurality of reservoirs containing a
separate and distinct unit of the plurality of units; and a plurality of
openings separately and respectively associated with the plurality of
separate reservoirs for providing fluid communication to the plurality of
reservoirs; and a plurality of doors for separately and respectively
covering the plurality of openings wherein each door of the plurality of
doors is opened at a separate and distinct point in time to provide for
separate release of the separate and distinct units over an extended
period of time.

7. A device as in claim 6 wherein the plurality of doors are formed of an
erodible material that is configured to erode is a manner that allows the
distinct units to exit the annular body at separate and distinct periods
of time.

8. A device as in claim 7 further comprising an electrical energy source
associated with the annular body and an anode and a cathode associated
with each of the plurality of openings wherein electrical energy sources
provide energy to the anode and cathode to aid in eroding the erodible
material of the doors.

9. A device as in claim 6 wherein the therapeutic composition includes a
prostaglandin.

10. A device as in claim 6 wherein the device, the annular body or both
include a contact surface that is shaped and sized to correspond to and
contact the conjunctiva of the human eye upon application of the device
to the eye.

11. A device as in claim 10 wherein the contact surface of the device
including all portions that contact the conjunctiva has a surface area
that is at least 77 mm2 and is typically no greater than 220
mm.sup.2.

12. A device as in claim 11 wherein the device has a volume that is at
least at least 14 mm3 and is no greater than 100 mm.sup.3.

13. An ophthalmic pericorneal drug delivery device, comprising; an
annular body sized and shaped to reside upon a conjunctiva of a human eye
and extend substantially entirely about a cornea of the human eye when
the annular body is disposed upon the human eye; a therapeutic
composition associated with the annular body wherein the therapeutic
composition is disposed as multiple separate distinct units in a single
reservoir within the annular body; an electromechanical device connected
to the annular body; and at least one opening for providing fluid
communication between the single reservoir and an environment external of
the device wherein the electromechanical device moves each unit to the at
least one opening at a separate point in time over an extended time
period.

14. A device as in claim 13 wherein each of the separate and distinct
units comprises a polymeric shell defining at least one reservoir wherein
the therapeutic composition is disposed in the at least one reservoir of
the polymeric shell of each of the separate and distinct units.

15. A device as in claim 13 wherein the separate and distinct units
comprise a body with a therapeutic composition coated thereon.

16. A device as in claim 13 wherein the separate and distinct units
comprise a is polymeric matrix with therapeutic composition dispersed
throughout the matrix.

17. A device and in any of claims 13 through 16 wherein the reservoir is
annular and the separate and distinct units are distributed about the
reservoir.

18. A device and in claim 13 wherein the therapeutic composition includes
a prostaglandin.

19. A device and in claim 13 wherein the device, the annular body or both
include a contact surface that is shaped and sized to correspond to and
contact the conjunctiva of the human eye upon application of the device
to the eye.

20. A device as in claim 19 wherein the contact surface of the device
including all portions that contact the conjunctiva has a surface area
that is at least 77 mm2 and is typically no greater than 220
mm.sup.2.

21. A device as in claim 20 wherein the device has a volume that is at
least at least 14 mm3 and is no greater than 100 mm.sup.3.

22. A method of treating an ophthalmic disease comprising: disposing a
device as in claim 1 on the conjunctiva of the eye.

23. A method as in claim 22 wherein the device is disposed and maintained
upon the eye without the use of any mechanical fastening elements that
extend into the eyeball.

24. A method as in claim 23 wherein the device is maintained upon the eye
for an extended period of time that is at least 24 hours.

25. A method of treating an ophthalmic disease comprising: disposing a
device as in claim 6 on the conjunctiva of the eye.

26. A method of treating an ophthalmic disease comprising: disposing a
device as in claim 13 on the conjunctiva of the eye.

Description:

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This present application is a divisional of U.S. patent application
Ser. No. 13/012,885 filed Jan. 25, 2011 which claims priority to U.S.
Provisional Patent Application No. 61/298,577, filed Jan. 27, 2010, the
entire contents of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates generally to the field of ocular
devices, pharmaceutics, and methods of drug delivery to the eye. More
particularly, it concerns pulsatile peri-corneal ocular devices for the
sustained pulsatile delivery of a therapeutic compound to the eye.

BACKGROUND OF THE INVENTION

[0003] The pharmaceutical industry has developed a variety of techniques
for delivering ophthalmic compositions, particularly those that include
therapeutic agents, to the eye. Typical ophthalmic drug delivery
techniques include topical application of ophthalmic compositions to the
eye (e.g., by drops directly onto the eye) and intravitreal injections,
which involve delivery of ophthalmic compositions to the vitreous of the
eye with a needle (e.g., a syringe). Both of these techniques have
drawbacks. One particular drawback common to both of these techniques is
the frequency with which an individual must apply the ophthalmic
compositions to best treat ophthalmic maladies such as glaucoma, age
related macular degeneration (AMD) and others. Patients often forget or
otherwise fail to administer drops to their eyes and patients can miss
doctor appointments and fail to receive their needed injections.

[0004] In view of these drawbacks, the pharmaceutical industry has
dedicated significant resources to the development of implantable drug
delivery devices that provide sustained delivery of ophthalmic
compositions and/or therapeutic agents to the eye. Such devices are
typically designed to provide a continuous supply of therapeutic agent to
the eye over an extended period of time.

[0005] Various ocular drug delivery implants have been described in an
effort to improve and prolong drug delivery. For example, U.S. Pat. No.
3,949,750 discloses a punctal plug made of a tissue-tolerable, readily
sterilizable material, such as Teflon, HEMA, hydrophilic polymer, methyl
methacrylate, silicone, stainless steel or other inert metal material. It
is stated that the punctal plug may be impregnated with ophthalmic
medication or that the punctal plug may contain a reservoir of the
ophthalmic drug.

[0006] U.S. Pat. No. 5,053,030 discloses an intracanalicular implant that
can be used as a carrier or medium for distributing medications
throughout the body. U.S. Pat. No. 5,469,867 discloses a method of
blocking a channel, such as the lacrimal canaliculus by injecting a
heated flowable polymer into the channel and allowing it to cool and
solidify. The polymer may be combined with a biologically active
substance that could leach out of the solid occluder once it has formed
in the channel.

[0007] WO 99/37260 discloses a punctal plug made of a moisture absorbing
material, which is not soluble in water, such as a modified HEMA. It is
also disclosed that an inflammation inhibitor, such as heparin, may be
added to the material from which the punctal plug is made.

[0008] U.S. Pat. No. 6,196,993 discloses a punctal plug containing
glaucoma medication. The medication is contained in a reservoir within
the plug. The reservoir is in fluid communication with a pore through
which the medication is released onto the eye.

[0009] U.S. Pat. No. 4,592,752 discloses a corneal drug delivery device.
The device is substantially the size and curvature of the cornea upon
which it is placed and it includes an aperture substantially the size and
shape of the pupil of the eye.

[0010] More recently, implantable devices have been developed for
providing pulsatile or intermittent doses of therapeutic agent to the
eye. Examples of such devices are disclosed in U.S. Pat. Nos. 5,725,493;
5,830,173; and 6,251,090 and U.S. Patent Publication No. 2008/0039792,
all of which are specifically incorporated herein by reference for all
purposes.

[0011] U.S. Patent Application No. 2008/0181930 discloses a drug delivery
device having a body that includes a matrix of a therapeutic agent and
another material such as silicon. The body is coated with a material such
as parylene and one or more pores extend from the outer surface of the
coating to the outer surface of the body to allow for release of
therapeutic agent.

[0012] U.S. Provisional Patent Application No. 61/157,010, which is
incorporated herein by reference for all purposes, discloses a
pericorneal drug delivery device. A preferred embodiment of the device
includes an inner matrix core surrounded by an outer coating. The outer
coating includes one or more openings extending to the core for allowing
sustained drug release from the inner matrix core.

[0013] Each of these devices can provide for some degree of sustained
delivery of an ophthalmic composition. However, these devices, as well as
other conventional devices, typically suffer from one or more drawbacks.
As one example, many conventional devices require that they be applied
through an invasive surgical procedure. As another example, many
conventional devices have difficulty delivering desired amounts of
therapeutic agent for desired amounts of time. As another example, many
conventional devices have difficulty delivering therapeutic agent in
particular quantities at particular times as may be needed or desired. As
yet another example, many devices have difficulty maintaining their
desired location relative to the eye and can be lost or undesirably
moved. As still another example, many conventional devices can cause
discomfort. Thus, there is a need for an ophthalmic drug delivery device
that can overcome one, two or more of these drawbacks.

SUMMARY OF THE INVENTION

[0014] The present invention is directed to an ophthalmic pulsatile
pericorneal drug delivery device. The device includes an annular body
sized and shaped to reside upon a conjunctiva of a human eye and extend
substantially entirely about a cornea of the human eye when the annular
body is disposed upon the human eye. The device further includes a
therapeutic composition associated with the annular body. The therapeutic
composition is preferably divided into a plurality of separate and
distinct units. The device also includes at least one opening for
releasing the therapeutic composition wherein the therapeutic composition
is released through the at least one opening topically to the eye as
multiple separate doses through repeated release of one or more of a
plurality of separate and distinct units. In a preferred embodiment, the
therapeutic composition in divided into the plurality of separate and
distinct units within the device or annular body and/or prior to release
from the device.

[0015] The device, the annular body or both can include a contact surface
that is shaped and sized to correspond to and contact the conjunctiva of
the human eye upon application of the device to the eye. That contact
surface of the device including all portions that contact the conjunctiva
will typically have a surface area that is at least 77 mm2 and is
typically no greater than 220 mm2. Preferably, the device has a
volume that is at least at least 14 mm3 and is no greater than 100
mm3.

[0016] In one embodiment, the annular body includes a plurality of
separate reservoirs, each of the plurality of reservoirs containing one
of the separate and distinct unit of the plurality of units, In such an
embodiment, the device will also include a plurality of openings
separately and respectively associated with the plurality of separate
reservoirs for providing fluid communication to the plurality of
reservoirs and will includes a plurality of doors for separately and
respectively covering the plurality of openings. Preferably each door of
the plurality of doors is opened at a separate and distinct point in time
to provide for separate release of the separate and distinct units over
an extended period of time. In one preferred embodiment, the plurality of
doors are formed of an erodible material that is configured to erode is a
manner that allows the distinct units to exit the annular body at
separate and distinct periods of time.

[0017] The present invention is also directed to a method of treating an
ophthalmic disease. Accordingly, the device can be disposed upon the eye
to intermittently release therapeutic composition topically to the eye.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The accompanying drawings, which are incorporated in and constitute
a part of this specification, illustrate several embodiments of the
invention and together with the description, serve to explain the
principles of the invention.

[0019]FIG. 1 is a perspective view of an exemplary peri-corneal drug
delivery device structure suitable for use with the invention of the
present application.

[0020]FIG. 2 is a perspective view of the structure of FIG. 1 shown as
applied to an eye.

[0021]FIG. 3 is a perspective view of one embodiment of a pulsatile
peri-corneal drug delivery device in accordance with an aspect of the
present invention.

[0022] FIG. 4 is a perspective view of another embodiment of a pulsatile
peri-corneal drug delivery device in accordance with an aspect of the
present invention.

[0023] FIG. 5 is a perspective view of yet another embodiment of a
pulsatile peri-corneal drug delivery device in accordance with an aspect
of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention is predicated upon the provision of a
pulsatile peri-corneal drug delivery device. The device is typically
annular and is configured to be disposed upon the conjunctiva and/or
cornea and, preferably, substantially extends about and/or substantially
surrounds the cornea. The device will include a mechanism for assisting
the device in providing pulsatile release (i.e., release of separate and
distinct units or doses) of therapeutic composition to the eye,
particularly the corneal surface of the eye, of a mammal (e.g., a human
being) from one or more reservoirs of therapeutic composition. The
mechanism will typically allow for pulsatile release from a single
reservoir or multiple reservoirs of therapeutic composition.

[0025] In one embodiment, the pulsatile drug delivery device includes
either a single reservoir of therapeutic composition which contains all
of the doses of the therapeutic composition or includes multiple
reservoirs of therapeutic composition where each of the multiple
reservoirs includes multiple doses of therapeutic composition. In such an
embodiment, the mechanism for assisting in providing pulsatile release
will typically include one or more openings that provide fluid
communication between the reservoir[s] and an environment external the
device. The mechanism will also typically include a door that can be
selectively opened and closed to allow release of the therapeutic
composition from the reservoir[s]. Preferably, the door[s] can be opened
and closed to allow for the release of multiple separate single doses of
the therapeutic composition over an extended time period.

[0026] In an alternative embodiment, the therapeutic composition is
divided within the device into multiple separate distinct units wherein
each of the units or a subset of the multiple units preferably provides a
single dose of therapeutic composition. In such an embodiment, the
mechanism for assisting in providing pulsatile release will typically
include one or more openings that provide fluid communication between one
or more reservoirs and an environment external the device. The multiple
separate units can be located within a single reservoir or multiple
reservoirs within the device. For example, each unit of the multiple
units may be located within its distinct reservoir of multiple reservoirs
of the device and be releasable as a single dose. Alternatively, multiple
units may be located within a reservoir where each unit is separately
releasable from the device to form a single dose. In embodiments where
one unit or a subset of the multiple units are disposed in multiple
different reservoirs, the mechanism for assisting in providing pulsatile
release will typically include one or more openings for each separate
reservoir to provide fluid communication thereto and one or more doors
for at least temporarily prohibiting and then subsequently allowing fluid
communication between the reservoir[s] and an environment external the
device in embodiments where the multiple different units are in a single
reservoir, their may only need be a single opening to provide for fluid
communication between the reservoir and an environment external the
device. Moreover, a door will typically be optional for prohibiting and
then subsequently allowing the fluid communication.

[0027] It should be understood, that the terms "separate" and "distinct",
as they apply to the units and doses of therapeutic composition, have
particular meaning for the devices of the present invention. As they
apply to units, those terms suggest there is an identifiable physical
element that separates the units. That physical element could be a
physical space that is between and separates the units. Alternatively,
that physical element could he an interface where one of the units abuts
the other. It is contemplated that the "separate" and/or "distinct" units
may be connected to each other, however, the physical element dividing
the units from each other will always exist. Preferably, the units are
unconnected relative to each other and may not even contact each other
particularly while in the one or more reservoirs of the device. As these
terms apply to doses, they mean that one dose will be substantially
completely released (i.e., at least 90% and more preferably at least 95%
by weight of the therapeutic composition has been released) to the
environment external of the device, which will typically be tear fluid or
film external of the eye, before a separate and/or distinct dose begins
release to the environment external of the device.

[0028] With reference to FIGS. 1 and 2, there is illustrated an annular
peri-corneal structure 10 that, as will be seen from the description of
the exemplary devices of FIGS. 3 through 5, can serve as a base structure
10 into which the therapeutic composition can be integrated. The device
10 is generally annular and, in the embodiment illustrated, is annular
about a central axis 18 and lies in a plane 20 that is perpendicular to
that axis. As used herein, the term "annular" as it is used to describe
the drug delivery device or structure thereof does not require that the
device be a continuous uninterrupted ring but must form substantially an
entire ring that can sufficiently extend about the cornea and/or
conjunctiva of the eye to maintain the device upon the conjunctiva once
provided to an individual. Preferably the annular device forms or
substantially forms a ring (i.e., forms at least 60% and more preferably
at least 80% of a ring that is designed to extend about the cornea). It
should be understood that the area internal to the annular device is
typically entirely open allowing for clear vision. However, it is
contemplated that a material may be located internal of the annular
device. For example, a clear polymeric film material (e.g., a contact
lens material or material like a contact lens) might be located internal
of the annular device and connected to the device.

[0029] In the embodiment shown, the structure 10 is in a continuous ring
or band having an inner diameter 22 and an outer diameter 24. Moreover,
the illustrated structure 10 is substantially or entirely symmetrical
about the central axis 18. The inner diameter is typically configured to
be directly adjacent the cornea upon application of the device to the
eye. A portion of the device may reside upon the outer periphery of the
cornea, but this is typically not desired. The inner diameter of the
device is typically at least 0.3 centimeter (cm), more typically at least
0.6 cm and even more possibly at least 0.9 cm and is typically no greater
than 1.5, more typically no greater than 1.3 cm and even more typically
no greater than 1.1 cm. The outer diameter is typically at least 0.6 cm,
more typically at least 1.1 cm and even more possibly at least 1.3 cm and
is typically no greater than 2.2, more typically no greater than 1.9 cm
and even possibly no greater than 1.7 cm. It should be understood that,
for individuals with smaller eyes such as children at ages approximately
3 to 10, these sizes may be reduces by 5 to 20%.

[0030] The structure 10 generally has an outer surface 26. That outer
surface 26 includes a first surface 28, which is a contacting surface
that contacts the conjunctiva of the eye when the structure 10 is placed
atop the conjunctiva. The structure 10, and particularly the outer
surface 26, also includes a second surface 30 that is opposite the first
surface 28. The second surface 30 is an outwardly facing surface that
faces away from the conjunctiva upon placement of the device 10 thereon.
The first surface 28 can be flat or slightly concave. The second surface
30 can be flat or slight convex. Both the first surface 28 and the second
surface 30 are disposed at an angle 34 relative to the plane 20 in which
the device 10 lies. That angle 34 may be different for different portions
of the surface[s] 26, 28, but is typically at least about 3°, more
typically at least about 10° and even possibly at least about
20° and is also typically no greater than about 60°, more
typically no greater than about 45° and even possibly no greater
than about 30°.

[0031] The structure of the device is preferably formed of a
non-biodegradable polymer that is substantially or entirely impermeable
to the therapeutic composition. Examples of potential materials suitable
for the structure include, without limitation, ethylene vinyl acetate
(EVA), polyacrylic materials (e.g., PMMA), silicone, polyimide,
polytetrafluoroethylene (PTFE), combination thereof or the like. In a
highly preferred embodiment, the structure is formed of parylene. As used
herein, "substantially impermeable" as it applies to the structure
material and the therapeutic composition means that less than 5% and more
typically less than 2% of the therapeutic composition permeates into the
structure material during the use of the device once applied to an eye of
an individual.

[0032] With reference to FIG. 3, there is illustrated one exemplary
embodiment of a pulsatile peri-corneal drug delivery device 40 in
accordance with the present invention. As can be seen, the device 40 has
the structure 10 substantially described relative to FIGS. 1 and 2. The
device 40 includes multiple reservoirs 42 that each contains a separate
and distinct unit 44 of therapeutic composition. Each of the reservoirs
42 is also associated with an opening 46 that can provide for fluid
communication between the reservoir 42 and the environment external of
the reservoir 42 and the device 40. A plurality of doors 48 is then
associated respectively with each of the plurality of openings 46 for
controlling flow of fluid through the openings 46. The device 40 also
includes an electrical supply 48 (e.g., a battery or battery and
controller) and electrical connections 50 that connect to the electrical
supply 48 and are connected to or associated with the doors 48.

[0033] Typically, the device 40 will include at least 3, more typically at
least 10, even more typically at least 60 and even more typically at
least 180 and even possibly at least 360 or even at least 600 units 44.

[0034] In operation (i.e., after application of the device to an eye of a
mammal, particularly a human being), the electrical supply sends
electrical current through the connections 50. That electrical current
then opens the doors 48 to allow fluid communication between the
reservoirs 42 and the environment outside the device 40 to allow the
distinct units 44 to be separately released as doses of therapeutic
composition at separate points in time. Preferably, each door 48 is
configured to allow such fluid communication starting at a separate and
distinct point in time. For example, after a first door 48 of the
multiple doors 48 opens to provide such fluid communication, each
subsequently opening door 48 of the remaining multiple doors 48 will
provide such fluid communication at least 60 minutes, more typically at
least 8 hours, still more typically at least 10 hours and even possibly
at least 20 or even 30 hours after a previously opening door 48 of the
multiple doors 48 provides such fluid communication. Such a progression
of opening doors 48 will typically continue over an extended period of
time.

[0035] It is contemplated that the electrical current may open the doors
by a variety of mechanisms. Typically, the electrical connections will
include an anode and cathode that can induce a charge on opposite side of
the door and/or can run the electrical current through the door. In that
instance, the doors may be formed of material that erodes or melts upon
exposure to the electrical current. Alternatively, the doors could be
formed of a material that is drawn toward the anode or cathode upon
exposure to electrical charge. The doors could also be formed of a
material (e.g., a metal or polymeric material) that vaporizes upon
exposure to electrical current or charge.

[0036] With reference to FIG. 4, there is illustrated another exemplary
embodiment of a pulsatile peri-corneal drug delivery device 60 in
accordance with the present invention. As can be seen, the device 60 has
the structure 10 substantially described relative to Figs. I and 2. The
device 60 includes multiple reservoirs 62 that each contains a separate
and distinct unit 64 of therapeutic composition. Each of the reservoirs
62 is also associated with an opening 66 that can provide for fluid
communication between the reservoir 62 and the environment external of
the reservoir 62 and the device 60. Each of the openings 66 is initially
blocked from such fluid communication by a door 68.

[0037] In FIG. 4, each of the doors 68 is formed of a bio-erodible
material. Examples of such bio-erodible materials include, without
limitation, polylactic acids, polyglycolic acids, polylactic-glycolic
acids, poly caprolactones, triglycerides, polyethylene glycols, poly
orthoesters, poly anhydrides, polyesters, cellulosics and combinations
thereof Moreover, such materials may be applied and may be applied in one
or multiple layers by a variety of techniques such as coatings, brushing
or the like. In one preferred embodiment, the material of the doors is
applied in multiple layers by repeat spray coating and/or drying. It is
noted that the doors 68 shown in FIG. 4 are shown in a magnified manner
to show them as having different layers. However, it should be understood
that the layers will not typically extend outwardly any significant
distance from the annular body of the device and are preferably located
within the openings 66 to the reservoirs 62.

[0038] In operation (i.e., after application of the device to an eye of a
mammal, particularly a human being), the doors 68 erode away to allow
fluid communication between the reservoirs 62 and the environment outside
the device 60 to allow the distinct units 64 to be separately released as
doses of therapeutic composition at separate points in time. Preferably,
each door 68 is configured to allow such fluid communication starting at
a separate and distinct point in time. For example, after a first door 68
of the multiple doors 68 opens to provide such fluid communication, each
subsequently opening door 68 of the remaining multiple doors 68 will
provide such fluid communication at least 60 minutes, more typically at
least 8 hours, still more typically at least 10 hours and even possibly
at least 20 or even 30 hours after a previously opening door 68 of the
multiple doors 68 provides such fluid communication. Such a progression
of opening doors 68 will typically continue over an extended period of
time.

[0039] In the embodiment shown, each of the doors 68 is shown to have a
different thickness. In this manner, the bioerodible material of the
doors 68 is configured to allow for fluid communication as described in
the preceding paragraph. Preferably, the first door 68 to allow fluid
communication will have a thickness (T1). Then each subsequently
opening door will have a thickness according to the following equation:

T=T1(N+1)F

[0040] wherein:

[0041] (N) is number of doors 68 that are, or are configured to open and
provide or allow fluid communication prior to that subsequently opening
door 68; and

[0042] (F) is any number greater than 0.1 but less than 10 and may be
different for each subsequently opening door.

[0043] It should be understood that (F) is a variable of the equation that
allows for variations in bio-erosion rates and/or preselected pattern of
release of the units of therapeutic composition. Typically, the device
will include at least 3, more typically at least 10, even more typically
at least 60 and even more typically at least 180 and even possibly at
least 360 or even at least 600 units 44 and/or reservoirs 42.

[0044] With reference to FIG. 5, there is illustrated yet another
exemplary embodiment of a pulsatile peri-corneal drug delivery device 80
in accordance with the present invention. As can be seen, the device 80
has the structure 10 substantially described relative to FIGS. 1 and 2.
The device 80 includes multiple distinct units 82 of therapeutic
composition located within a single annular reservoir 84 that extends
substantially entirely about the structure 10. As can be seen, the units
are unconnected relative to each other. As can be seen, the distinct
units 82 are distributed along the reservoir 84 one after the other. In
the particular embodiment shown, spacer units 86 separate the distinct
units 82 from each other. When used, the spacer units 86 can aid discrete
and separate dispensing and delivery of the distinct units 82 of
therapeutic composition.

[0045] The device 80 of FIG. 5 also includes an opening 90 and an
electromechanical mechanism 92 for providing for fluid communication
between at least a portion of the reservoir 84 and the environment
external of the reservoir 84 and the device 80. As can be seen, the
electromechanical mechanism 92 can move the discrete units 82 and/or the
spacer units 86 about the reservoir 84 to individually align each
discrete unit 82 with the opening 90. Once a discrete unit 82 has been
aligned with the opening 90, fluid communication between the reservoir 84
and the external environment of the device 80 through the opening 90
allows the discrete unit 82 to release its therapeutic composition to
that external environment (e.g., tear fluid can enter the reservoir 84
through the opening 90 to allow for such release). Preferably, the
electromechanical mechanism 92 is pre-programmed to move the units 82 a
separate distinct points in time.

[0046] The discrete units 82 can be formed in a variety of configurations
that will allow them to relatively rapidly release therapeutic
composition when the unit 82 is aligned with the opening 90. In a
preferred embodiment, the discrete units are comprised of a
non-biodegradable material (e.g., polymeric material) that includes one
or more openings and or reservoirs for containing and then releasing the
therapeutic composition. As one example, the discrete unit 82 can
comprise a shell (e.g., a polymeric shell) substantially surrounding a
reservoir, which contains the therapeutic composition in a solid, but
dissolvable, form. In such an embodiment the shell will typically include
one or more openings such that fluid (e.g., tear fluid) can enter the
opening[s] and/or reservoir and dissolve the therapeutic composition,
which can then be released from the polymeric shell. As another example,
the discrete unit 82 comprises a non-erodible body that has a coating of
therapeutic composition on it and fluid (e.g., tear fluid) can dissolve
the therapeutic composition, which can then be released from the body. In
such an embodiment, the coating of therapeutic composition could include
a polymeric material that is either erodible or non-erodible, but which
can aid in controlling the rate of release of the therapeutic composition
from the distinct unit. As still another example, the discrete unit 82
comprises a non-erodible matrix (e.g., polymeric matrix) within which a
therapeutic composition has been dispersed. In such an embodiment, the
therapeutic composition can permeate out of the matrix when it is exposed
to fluid (e.g., tear fluid) adjacent the opening of the device.
Typically, the device 80 will include at least 3, more typically at least
10, even more typically at least 60 and even more typically at least 180
and even possibly at least 360 or even at least 600 units 84.

[0047] A variety of mechanisms may be suitable for use as the
electromechanical mechanism 92 for the device 80. For example, a small
electrical powered gear system might be used to advance the units 82.
Alternatively, a small magnetic system could be used to advance the units
82. Preferably, the mechanism includes a controller for controlling the
system such that it advances the units 82 at predetermined times.

[0048] In operation (Le., after application of the device to an eye of a
mammal, particularly a human being), the discrete units 82 are
individually moved to the opening 90 to progressively allow fluid
communication between each of the units 82 and the environment outside
the device 80 to allow the distinct units 82 to separately release doses
of therapeutic composition at separate points in time. Preferably, each
of the units 82 are moved about the reservoir 84 to align one of the
units with the opening 82 at distinct points in time that are at least 60
minutes, more typically at least 8 hours, still more typically at least
10 hours and even possibly at least 20 or even 30 hours apart from each
other to allow each of the units to release therapeutic composition to
the environment outside the device 80. Such a progression of release from
the units 82 will typically continue over an extended period of time.

[0049] In an alternative configuration, it is contemplated that the device
of the present invention can configured substantially identical to the
device 80 of FIG. 5 with minor exceptions. The therapeutic composition
can be provided as a single, preferably liquid, mass or supply that can
be released through the opening 90 as separate and distinct units. In
such an embodiment, the flow through the opening would be controlled by a
door or valve that would allow for release of portions of the single mass
or supply of therapeutic compositions at separate points in time to form
the separate and distinct doses or units.

[0050] The therapeutic composition of the present invention will typically
include a therapeutic agent and may be consist or consist essentially of
only therapeutic agent. Alternatively, the therapeutic composition can
include one or more excipients such as, surfactant, tonicity agent,
carrier such as water, polymeric material (e.g., biodegradable polymeric
material), antimicrobial agent, buffering agents, combinations thereof or
the like. The therapeutic composition may be provided as a liquid,
semi-solid or solid, which will typically depend upon the type of
discrete units, door[s] and/or reservoir[s] used with the device.
Preferably, the therapeutic composition, particularly the therapeutic
agent, is in a condition that allows it to, upon release from the device
to the environment external the eye (e.g., to the tear fluid). The
therapeutic composition, particularly the therapeutic agent, can then
move with the tear fluid to the conjunctiva and/or to the cornea and/or
to the back of the eye. The therapeutic composition, particularly the
therapeutic agent, can then penetrate into the eye or treat a surface
disease of the eye.

[0051] The therapeutic agent (e.g., ophthalmic drug) may be any
therapeutic agent, so long as the therapeutic agent is capable of
providing a therapeutic effect to the eye of a mammal, particularly a
human. In particular embodiments, the therapeutic compound is a compound
that can be applied for the treatment of an ophthalmic disorder. For
example, the therapeutic compound may be a glaucoma medication, an
antimicrobial medication, an anti-inflammatory medication, or a dry-eye
syndrome medication, or a therapeutic compound that can be applied in the
treatment of diabetic retinopathy or age-related macular degeneration.

[0052] Ophthalmic drugs, such as prostaglandins, triamcinolone, 15-HETE
(Icomucret), anti-inflammatories (non-steroidal anti-inflammatory drugs
(NSAIDs)) receptor tyrosine kinase inhibitors (RTKi), timolol maleate,
fluoroquinolones (e.g., moxifloxacin) and rimexolone, are well suited for
delivery with the devices of the present invention. The prostaglandin may
be a natural or a synthetic prostaglandin. Non-limiting examples of
prostaglandins include cloprostenol, fluprostenol, latanoprost,
travoprost, and unoprostone.

[0053] It is also contemplated that the device of the present invention
may be use to deliver multiple therapeutic agents. For example, for one
device, a first one or subset of the distinct doses or units may include
a therapeutic composition having a different therapeutic agent than
another second one or subset or subset of distinct doses or units.
Moreover, those units can be delivered at any distinct points in time to
provide a desired therapy.

[0054] According to certain aspects of the present invention, the
opening[s] that allow for fluid communication to the reservoir[s] and/or
therapeutic composition are located only on the surface of the device
that contacts the conjunctiva of the eye. Alternatively, the opening[s]
can be located only on the surface facing away from the conjunctiva of
the eye. As still another alternative, opening[s] may be located on both
surfaces. Having opening[s] facing away from the conjunctiva can be
particularly desirable for delivery of anti-glaucoma or intraocular
pressure lowering therapeutic agents such as a prostaglandin (e.g.,
cloprostenol, fluprostenol, latanoprost, travoprost, and unoprostone).
This allows the therapeutic agent to diffuse into the tear fluid and from
the tear fluid through the cornea to the iris ciliary body. Having
opening[s] that face arid/or contact the conjunctiva can be particularly
desirable for therapeutic agents that act at the posterior of the eye and
can benefit from improved delivery to the vitreous. Such drugs can
include anti-inflammatories, particularly NSAIDs such as nepafenac or
diclofenac.

[0055] In certain aspects, the devices of the present invention deliver
multiple separate therapeutically effective doses of the therapeutic
composition to a mammal, particularly a human being, over an extended
time period. As used herein, the phrase "extended time period" is no less
than 12 hours, but is typically at least about 24 hours, at least about 5
days, at least about 20 days, at least about 30 days, at least about 60
days, at least about 90 days, at least about 120 days, at least about 180
days, at least about 240 days or any range derivable therein. In
particular embodiments, the devices of the present invention deliver the
therapeutically effective doses of the therapeutic composition for at
least 10 days.

[0056] Advantageously, the device of the present invention can provide
desirable dosage amounts of therapeutic agent during the above referenced
extended time periods. Generally, the device can typically deliver doses
that includes at least 0.01 μg, more typically at least 0.1 μg and
even more typically at least 0.6 μg of therapeutic agent per dose or
distinct unit. The device also typically delivers no greater than 1000
μg, more typically no greater than 400 μg and still more typically
no greater than 150 μg of therapeutic agent per dose or distinct unit.
For higher potency drugs such as prostaglandins, the device is typically
configured to deliver from about 0.4 μg to about 2.0 μg of
therapeutic agent per dose or distinct unit. For medium potency drugs,
the device is typically configured to deliver from about 5 to about 20
μg. For lower potency drugs, the device is typically configured to
deliver from about 30 μg to about 120 μg of therapeutic agent per
dose or distinct unit.

[0057] In one embodiment, the present invention provides a method of
treating an ocular disorder in a subject comprising: (a) forming a drug
delivery device as described herein for the sustained release of multiple
separate doses of therapeutic composition to the eye; and (b) disposing
the device upon an external surface (e.g., surface of the conjunctiva) of
the eye. The method can be specifically for treating glaucoma or ocular
hypertension in a subject (e.g., a human) and the therapeutic agent can
be, for example, a prostaglandin.

[0058] In some embodiments, biodegradable microspheres of the therapeutic
agent are formed for creating the whole or a part of the therapeutic
composition. Microspheres, microcapsules and nanospheres (collectively,
"microspheres") are generally accepted as particles with diameters
ranging from approximately 50 nm to 1000 micrometers. They are reservoir
devices that come in a variety of different forms, including, but not
limited to, porous, hollow, coated, or uncoated forms with a
pharmaceutically active agent either incorporated into or encapsulated by
polymeric material via numerous known methods. Such known methods
include, but are not limited to, spray drying, spinning disk and
emulsification methods. Microspheres may be formed from a myriad of
polymeric materials selected from, but not limited to, polylactic acids,
polyglycolic acids, polylactic-glycolic acids, poly caprolactones,
triglycerides, polyethylene glycols, poly orthoesters, poly anhydrides,
polyesters, cellulosics and combinations thereof. The amount of
therapeutic agent incorporated or encapsulated in the microsphere is
generally between 0.001% and about 50%.

[0059] The device can be configured to have a relatively large external
surface area, which allows the device to be maintained upon the
conjunctiva more securely. In particular, capillary forces of the fluid
upon the conjunctiva can aid in maintaining the device upon the eye. It
should be noted that, for purposes of this invention, the fluid located
upon the conjunctiva is considered to be part of the conjunctiva upon
which the device can be located. The surface area of the contacting
surface as determined inclusive of any and every portion (including
haptics) of the device that contacts the conjunctiva is typically at
least 50 (millimeters squared) mm2, more typically at least 77
mm2, even more typically at least 90 mm2 and even possibly at
least 110 mm2 and the surface area of that portion is typically no
greater than 320 mm2, more typically no greater than 220 mm2,
even more possibly no greater than 170 mm2 and even possibly no
greater than 120 mm2.

[0060] Advantageously, it may be the case that the device of the present
invention can reside upon and be maintained upon the eye without needing
any fastening elements such as stitches or other mechanical devices that
extend into the eye (i.e. into the conjunctiva, cornea or any other
portion of the eyeball). Such fastening devices typically must be
surgically applied and avoidance of such surgical applications can be
desirable in many circumstances.

[0061] The device of the present invention can, in certain embodiments, be
relatively large such that it can include multiple doses or distinct
units of therapeutic composition. The volume of the entire device of the
present invention is typically at least 10 mm3, more typically at
least 14 mm3, and even more typically at least 18 mm3 and the
volume of the device is typically no greater than 100 mm3, more
typically no greater than 50 mm3, and even possibly no greater than
30 mm3. The weight of the entire device of the present invention is
typically at least 10 mg, more typically at least 14 mg, and even more
typically at least 17 mg and the weight of the device is typically no
greater than 1000 mg, more typically no greater than 100 mg, and even
more possibly no greater than 30 mg.

[0062] The use of the term "or" in the claims is used to mean "and/or"
unless explicitly indicated to refer to alternatives only or the
alternatives are mutually exclusive.

[0063] Throughout this application, the term "about" is used to indicate
that a value includes the standard deviation of error for the device or
method being employed to determine the value.

[0064] Following long-standing patent law, the words "a" and "an," when
used in conjunction with the word "comprising" in the claims or
specification, denotes one or more, unless specifically noted.

[0065] In this document (including the claims), the terms "comprise" (and
any form of comprise, such as "comprises" and "comprising"), "have" (and
any form of have, such as "has" and "having"), and "include" (and any
form of include, such as "includes" and "including") are open-ended
linking verbs.

[0066] Applicants specifically incorporate the entire contents of all
cited references in this disclosure. Further, when an amount,
concentration, or other value or parameter is given as either a range,
preferred range, or a list of upper preferable values and lower
preferable values, this is to be understood as specifically disclosing
all ranges formed from any pair of any upper range limit or preferred
value and any lower range limit or preferred value, regardless of whether
ranges are separately disclosed. Where a range of numerical values is
recited herein, unless otherwise stated, the range is intended to include
the endpoints thereof, and all integers and fractions within the range.
It is not intended that the scope of the invention be limited to the
specific values recited when defining a range.

[0067] Other embodiments of the present invention will be apparent to
those skilled in the art from consideration of the present specification
and practice of the present invention disclosed herein. It is intended
that the present specification and examples be considered as exemplary
only with a true scope and spirit of the to invention being indicated by
the following claims and equivalents thereof.

Patent applications by Alan L. Weiner, Arlington, TX US

Patent applications by Bhagwati P. Kabra, Euless, TX US

Patent applications in class Method of applying or removing material to or from body

Patent applications in all subclasses Method of applying or removing material to or from body